This application is a response to RFA OD-09-003, "Recovery Act Limited Competition: NIH Challenge Grants in Health and Science Research (RC1)." This application addresses broad Challenge Area (05), Comparative Effectiveness Research, and specific Challenge Topic, 05-AG-105 "Comparative Intervention Trials for Diseases and Syndromes of Aging including Neurodegenerative Diseases." Funding of this competing revision will enable the hiring of a total of 3.25 full time people: a half-time exercise physiologist, 1.5 postdoctoral fellows and a 1.25 research assistants. Perhaps the most urgent scientific challenge for the 21st century is to develop interventions to slow the process of cognitive aging so that at the end of life, most older adults are in control of their mental faculties and they and their families can enjoy a high quality of life in this final phase of human development. The focus of the present application is to examine carefully the role of lifestyle variables that are commonly believed to be "good for the mind" in facilitating healthy cognitive aging. There is clear evidence that physical exercise improves cognitive health in late adulthood. What has not been studied is whether enhancing neural vasculature through exercise is an important condition for reaping the benefits of cognitive interventions. One of the main reasons for this gap in knowledge is the cost of implementing and studying such complex lifestyle interventions. The proposed project is one of the first attempts to study the joint effects of exercise and a cognitive intervention program by adding exercise conditions to an already-funded intervention study on cognitive engagement in the laboratory of Denise Park at the Center for Brain Health in Dallas. Synapse involves investigating the impact on cognitive function of immersing adults in a 12 week new learning challenge for 15- 20 hours each week. Subjects learn to quilt, perform digital photography, or do both. In this new application, we will add two groups to the Synapse project for the next three years: an Exercise Only group that improves cardiovascular health through a walking program that will allow us to assess the impact of exercise versus cognitive engagement. We will also add an Exercise Plus Engagement group comprised of subjects that both exercise and participate in Synapse, allowing us to assess whether exercise potentiates cognitive engagement effects. Because the infrastructure costs of the Synapse project are already funded, we can address critical scientific questions about exercise and cognitive interventions which have proven to be too expensive to easily address in previous work. The two primary goals of the project are to (a) directly compare exercise interventions and cognitive interventions to determine relative effectiveness of each domain and (b) examine the interactive effects of a joint exercise/cognitive intervention program. We hypothesize that a healthy cardiovascular system will greatly enhance cognitive intervention effects. In addition, we will utilize novel and exceptionally sensitive measures of cerebrovascular fitness by employing transcranial Doppler imaging, a method that has not yet been used in the exercise/cognition domain. Besides measuring VO2-Max, we will measure cerebral hypoperfusion, blood vessel reactivity, and arterial stiffness so that we will have careful measures of vascular health. PUBLIC HEALTH RELEVANCE: The focus of the present application is to examine carefully the role of lifestyle variables that are commonly believed to be "good for the mind" in facilitating healthy cognitive aging. There is clear evidence that physical exercise improves cognitive health in late adulthood. What has not been studied is whether enhancing neural vasculature through exercise is an important condition for reaping the benefits of cognitive interventions. The proposed project is one of the first attempts to study the joint effects of exercise and a cognitive intervention program on cognition.